Project Summary/Abstract Almost two-thirds of Americans with Alzheimer?s disease and related dementias (AD/ADRD) are women. The underlying mechanisms are unknown but may be associated with a higher prevalence of hypertension and lower blood pressure (BP) control rate in older women than older men. Indeed, recent research implicates risk factors such as hypertension and cerebrovascular dysfunction in the pathogenesis of AD. Cerebrovascular function and cognition can be affected by BP dysregulation via the baroreflex, and baroreflex sensitivity is reduced in hypertension and AD - an effect that is likely related to cerebrovascular dysfunction and arterial stiffening. Thus, decreasing BP, increasing baroreflex sensitivity, and improving cerebrovascular health may be an important preventive strategy for AD/ADRD in older women with hypertension. One non-drug approach that offers promise is ?heat therapy?. The objective of this administrative supplement is to leverage our existing clinical trial in order to perform a proof-of-concept investigation to examine the effects of home-based lower leg heat therapy on AD/ADRD risk, as reflected by changes in cerebrovascular function in older hypertensive women. To accomplish this objective, we will enroll hypertensive women aged 65-79 and randomly assign them to either an intervention group or a control group. Patients in the intervention group will perform 8 weeks of home-based lower leg heat therapy via water immersion up to the knee in a circulated bath (water temperature 42C, 4 times per week, 45 min per session), whereas patients in the control group will immerse their legs in a thermoneutral water bath (33C) at the same frequency and duration. All patients will also receive a fixed dose of chlorthalidone. Aim 1 will examine the effect of heat therapy on cerebral hemodynamics in older hypertensive women. We will use transcranial Doppler to assess cerebral hemodynamics before and after heat therapy or control treatment. Dynamic cerebral autoregulation will be evaluated by transfer function analysis. Aim 2 will examine the mechanisms by which heat therapy impacts cerebral hemodynamics. We will measure ambulatory BP, sympathetic and cardiovagal baroreflex sensitivities, and dynamic arterial compliance, ?-stiffness index and wall thickness of the carotid artery. The associations among cerebral hemodynamics, BP, baroreflex sensitivity, and the carotid artery properties will be investigated. Aim 3 (exploratory) will examine the effects of heat therapy on cognition and blood-based biomarkers of AD pathology and neurodegeneration in older hypertensive women. We will use the NIH Toolbox Cognition Battery to assess cognitive function. Biomarkers of AD pathology and neurodegeneration will be measured in plasma samples obtained before and after heat therapy or control.